CN105541872A - Ortho-naphthaquinone derivative, and preparation method and medicinal application thereof - Google Patents
Ortho-naphthaquinone derivative, and preparation method and medicinal application thereof Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 239000003814 drug Substances 0.000 claims abstract description 12
- 201000011510 cancer Diseases 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 6
- 229930192627 Naphthoquinone Natural products 0.000 claims description 13
- 150000002791 naphthoquinones Chemical class 0.000 claims description 12
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical class C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- CSFWPUWCSPOLJW-UHFFFAOYSA-N lawsone Chemical class C1=CC=C2C(=O)C(O)=CC(=O)C2=C1 CSFWPUWCSPOLJW-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 238000004062 sedimentation Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- HMPUHXCGUHDVBI-UHFFFAOYSA-N 5-methyl-1,3,4-thiadiazol-2-amine Chemical class CC1=NN=C(N)S1 HMPUHXCGUHDVBI-UHFFFAOYSA-N 0.000 claims description 2
- OVWYEQOVUDKZNU-UHFFFAOYSA-N m-tolualdehyde Chemical compound CC1=CC=CC(C=O)=C1 OVWYEQOVUDKZNU-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 101000973778 Homo sapiens NAD(P)H dehydrogenase [quinone] 1 Proteins 0.000 abstract description 24
- 102100022365 NAD(P)H dehydrogenase [quinone] 1 Human genes 0.000 abstract description 24
- 238000012360 testing method Methods 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 11
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- 239000001301 oxygen Substances 0.000 abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 abstract description 8
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- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 230000004224 protection Effects 0.000 abstract description 4
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- 238000000338 in vitro Methods 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract description 2
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- 238000004519 manufacturing process Methods 0.000 abstract description 2
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- KETQAJRQOHHATG-UHFFFAOYSA-N 1,2-naphthoquinone Chemical class C1=CC=C2C(=O)C(=O)C=CC2=C1 KETQAJRQOHHATG-UHFFFAOYSA-N 0.000 abstract 2
- 230000003013 cytotoxicity Effects 0.000 abstract 1
- 231100000135 cytotoxicity Toxicity 0.000 abstract 1
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- 102000004190 Enzymes Human genes 0.000 description 7
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- WVCHIGAIXREVNS-UHFFFAOYSA-N 2-hydroxy-1,4-naphthoquinone Chemical compound C1=CC=C2C(O)=CC(=O)C(=O)C2=C1 WVCHIGAIXREVNS-UHFFFAOYSA-N 0.000 description 2
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- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
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- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 2
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- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- HARGZZNYNSYSGJ-UHFFFAOYSA-N 1,2 dihydrotanshinquinone Natural products C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)CO1 HARGZZNYNSYSGJ-UHFFFAOYSA-N 0.000 description 1
- WOAHJDHKFWSLKE-UHFFFAOYSA-N 1,2-benzoquinone Chemical class O=C1C=CC=CC1=O WOAHJDHKFWSLKE-UHFFFAOYSA-N 0.000 description 1
- 150000004869 1,3,4-thiadiazoles Chemical class 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
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- 102000018832 Cytochromes Human genes 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- HARGZZNYNSYSGJ-JTQLQIEISA-N Dihydrotanshinone I Chemical compound C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2[C@@H](C)CO1 HARGZZNYNSYSGJ-JTQLQIEISA-N 0.000 description 1
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- 101710157860 Oxydoreductase Proteins 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- DAEFUOXKPZLQMM-AUDZWCKFSA-N Squamocin Chemical compound O1[C@@H]([C@@H](O)CCC[C@@H](O)CCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 DAEFUOXKPZLQMM-AUDZWCKFSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
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- 230000004071 biological effect Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
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- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- KXNYCALHDXGJSF-UHFFFAOYSA-N dihydroisotanshinone I Natural products CC1=CC=CC2=C(C(C=3OCC(C=3C3=O)C)=O)C3=CC=C21 KXNYCALHDXGJSF-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
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- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
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- 208000020816 lung neoplasm Diseases 0.000 description 1
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- 239000002609 medium Substances 0.000 description 1
- 230000008558 metabolic pathway by substance Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 150000004053 quinones Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
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- 239000002904 solvent Substances 0.000 description 1
- DAEFUOXKPZLQMM-UHFFFAOYSA-N squamocin A Natural products O1C(C(O)CCCC(O)CCCCCC)CCC1C1OC(C(O)CCCCCCCCCCCCC=2C(OC(C)C=2)=O)CC1 DAEFUOXKPZLQMM-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to an ortho-naphthoquinone derivative, a preparation method and medical application thereof, and provides a compound with the structure shown as a formula I, a preparation method and application thereof in the manufacture of tumor medicaments. The compound of the invention has a hybrid structure of ortho -naphthoquinone with thiadiazole [3,2-a] pyrimidine, strong anti-cancer activity, metabolic stability and good selectivity. In vitro cytotoxicity and topoisomerase I inhibition tests show that the compound has strong inhibition on tested cancer cells and topoisomerase I; and NQO1 activity test shows that the compound is an effective substrate for NQO1, and mediated by NQO1, the compound cycles by a redox reaction, produces a large amount of reactive oxygen to induce oxidative stress, and selectively kills tumor cells. The compound can be used as an anti-cancer drug or a lead compound for further development. The method of the present invention has the characteristics of greenness, environmental protection, easily available raw materials, simple operation, and high yield.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a kind of adjacent naphthoquinone derivatives, comprise the purposes of this compounds process for production thereof and the medicine as preparation treatment malignant tumour.
Background technology
The health of the mankind in malignant tumour serious threat, capture and cure malignant tumour and become one of focus of world drug research, the antitumor drug finding efficient, low toxicity and high specificity is still the Main way of antitumor drug research, NQO1 is a kind of important phaseⅡreaction enzyme in body, participates in external source substance metabolism process in body by de-electronation reduction reaction.NQO1 and quinones substance detoxify, cancer therapy drug bioactivation, p53 protein stability regulate and the apoptosis-induced effect of TNF-α closely related, thus transformation, apoptosis and protection in play a significant role.The expression of NQO1 in kinds of tumor cells particularly lung cancer, colorectal carcinoma, breast cancer cell is far above healthy tissues.Due to the high expression level of NQO1 at tumour cell and the characteristic of bioactivation thereof, it is considered to the potential molecular target for the treatment of kinds of tumors.Adjacent naphthoquinone compound is a class chemical composition of natural extensive existence, has the multiple biological activitys such as antibacterial, antiviral, antitumor and anti-oxidant.Representative compound containing o-naphthaquinone has β-lapachol, MansononeE, dihydrotanshinone, Tanshinone II A and Squamocin A etc.The o-quinone compounds of nearest bibliographical information the type can be used as the substrate of NQO1 enzyme, by producing the method for active oxygen under the mediation of NQO1 enzyme, optionally kills tumour cell.
The multiple various active such as 1,3,4-thiadiazoles also [3,2-a] pyrimidines is the analog of guanozola, has anticancer, antibacterial, chemical compound lot is successfully developed as medicine and pesticide intermediate.Therefore, the synthesis of this compounds has been caused to the interest widely of pharmacy man.
In recent years, between pharmacophore or active compound, carry out rational molecular hybridization, as the New Policy of drug discovery, be subject to synthetic chemistry and Pharmaceutical Chemist is paid attention to greatly.Heterozygote compound generally has than the better avidity of parent compound and pharmacological action, is the effective way finding to have independent intellectual property right new chemical entities medicine.Innovation of the present invention is to have synthesized the heterozygote of a kind of adjacent naphthoquinones and thiadiazoles also [3,2-a] pyrimidine, and this compound not yet has report at present.Cell in vitro poison and topoisomerase I inhibition test show that this compound is to testing cancer cells and topoisomerase I all has stronger restraining effect, to test with the molecular docking of NQO1 and NQO1 activity experiment shows, this compound and NQO1 have higher affinity, can be activated by NQO1, produce active oxygen radical, selectively killing tumour cell, the cancer therapy drug that can be used as target topoisomerase I or NQO1 is developed further.
Summary of the invention
The object of the present invention is to provide a kind of adjacent naphthoquinone derivatives.
Another object of the present invention is to preparation method and medicinal use that described adjacent naphthoquinone derivatives is provided.
In order to realize the object of the invention, adjacent naphthoquinone derivatives of the present invention, it is for having the compound of structure shown in formula I:
I。
Specifically, adjacent naphthoquinone derivatives of the present invention is 5-aminomethyl phenyl-2-methyl-5H-benzo [i] [1,3,4] thiadiazoles also [3,2-a] quinazoline-6,7-diketone, molecular formula: C
21h
15n
3o
2s, molecular weight: 373.09, outward appearance: red brown solid.
The present invention also provides the preparation method of above-mentioned adjacent naphthoquinone derivatives, joins in round-bottomed flask by reactant 2 hydroxy 1,4 naphthoquinone (lawsone), 3-tolyl aldehyde, 5-methyl-2-amino-1,3,4-thiadiazoles and appropriate DMF, at 130 DEG C of reacting by heating 5-8 hour.After reacting completely, gained mixture is cooled to room temperature, adds water washing, sedimentation and filtration, column chromatography purification, obtain aminomethyl phenyl-2-methyl-5H-benzo [i] [1,3,4] thiadiazoles also [3,2-a] quinazoline-6,7-diketone between target compound 5-.
The reaction formula of preparation method of the present invention is:
Above-mentioned adjacent naphthoquinone derivatives provided by the invention is effective substrate of topoisomerase I inhibitor and bielectron oxydo-reductase NQO1, can be used for the targeted drug preparing treatment malignant tumour.
Advantage of the present invention and beneficial effect are:
1. heterozygote of the present invention has the structure of adjacent naphthoquinone derivatives, novel structure, has the selectivity that stronger antitumour activity is become reconciled;
2. the anti-tumor activity of the compounds of this invention and druggability are better than β-lapachol;
3. show that this compound all has stronger restraining effect to topoisomerase I with topoisomerase I inhibition test;
4. test with the molecular docking of NQO1 and NQO1 activity experiment shows, this compound and NQO1 have higher affinity, can be activated by NQO1, generation active oxygen radical, selectively killing tumour cell, and the cancer therapy drug that can be used as target NQO1 is developed further;
5. preparation method of the present invention has environmental protection, and raw material is easy to get, feature simple to operate.
Embodiment
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
The synthesis of embodiment 1 compound
Reactant 1.74g2-hydroxyl-1,4-naphthoquinone, 1.20g3-tolyl aldehyde, 1.15g5-methyl-2-amino-1,3,4-thiadiazoles and 10mL dimethyl formamide are joined in 50mL round-bottomed flask, at 130 DEG C of reacting by heating 5-8 hour.After reacting completely, gained mixture is cooled to room temperature, add the distilled water of 50mL, sedimentation and filtration, column chromatography purification, obtain aminomethyl phenyl-2-methyl-5H-benzo [i] [1 between corresponding reddish-brown product 5-, 3,4] thiadiazoles also [3,2-a] quinazoline-6,7-diketone 1.16g, productive rate is 31%.
1HNMR(400MHz,CDCl
3)δ:8.37(d,1H,J=8.0Hz),8.10(d,1H,J=7.6Hz),7.72(t,1H,J=7.6Hz),7.56(t,1H,J=7.6Hz),7.29-7.10(m,4H),6.59(s,1H),2.54(s,3H),2.32(s,3H);
13CNMR(100MHz,CDCl
3)δ:179.1,175.9,167.7,154.2,152.2,140.2,138.5,134.6,134.5,131.1,130.9,129.7,128.8,128.7,128.2,126.7,124.5,111.8,60.4,21.5,17.0；ESI-HRMSm/z[M+Na]
+:396.0773。
Embodiment 2 anti tumor activity in vitro is tested
Adopt the anti-tumor activity of mtt assay test target compound.With human liver cancer cell HepG2 and colon cancer cell HCT116 for test cell strain, select the attached tumor cells of logarithmic phase, after trysinization, the cell suspension of 5000/mL is made into the RPMIl640 substratum containing 10% calf serum, be seeded in 96 well culture plates, 200 μ L are inoculated in every hole, 37 DEG C, 5%CO
2cultivate 24h.Set up negative control group, positive controls and administration group.The substratum containing different concns sample that experimental group renews, control group then changes the substratum containing equal-volume solvent, and positive controls gives positive control drug Zorubicin, and (being diluted to concentration with perfect medium is 10 μm of olL
-1), often group establishes 3-5 parallel hole, 37 DEG C, 5%CO
2cultivate 4-5 days.Abandoning supernatant, every hole adds the freshly prepared serum free medium containing 0.2mg/mLMTT of 200 μ L.37 DEG C are continued cultivation 4 hours.Carefully abandoning supernatant, and add 200 μ LDMSO, after the mixing of miniature ultrasonic vibrator, microplate reader is 570nm with tested wavelength, and reference wavelength is that 450nm measures optical density value.Be calculated as follows the inhibiting rate of drug on tumor Growth of Cells: growth of tumour cell inhibiting rate %=(1-OD experiment/OD contrasts) × 100%.With aminomethyl phenyl-2-methyl-5H-benzo [i] [1 between 5-, 3,4] thiadiazoles also [3,2-a] quinazoline-6, the different concns of 7-diketone can obtain dose response curve to the mapping of growth of tumour cell inhibiting rate, therefrom obtains the half casualty-producing concentrations IC of sample
50.Its IC
50value is 3.39 μMs (HepG2), 3.57 μMs (HCT116).
Embodiment 3NQO1 active testing
Containing 25mMTris/HCl (pH7.4) in the reaction system of 1mL, 0.7mg/mL bovine serum albumin, 0.1%Tween-20,200 μMs of NADH, 77 μMs of Cytochromec, aminomethyl phenyl-2-methyl-5H-benzo [i] [1 between 2 μ g recombinant human NQOl and 5-, 3,4] thiadiazoles also [3,2-a] quinazoline-6,7-diketone (25 μMs).Setting determined wavelength 550nnm, at room temperature, adds NADH and starts reaction, calculate rate of reduction from the initial linear portion of response curve, by cytochrome c molar absorptivity conversion (21.1mM
-1cm
-1), result is expressed as a μm ol reduced form cytochrome c/min/ μ gNQOl.Can judge that compound produces the ability of active oxygen from the change of cytochrome c amount, the speed that compound produces active oxygen at enzyme level is 1202 ± 61 μm of ol reduced form cytochrome cs/min/ μ gNQOl.
Embodiment 4 molecular docking is tested
ChemBioDrawUltra12.0 is adopted to draw aminomethyl phenyl-2-methyl-5H-benzo [i] [1 between small molecules 5-, 3,4] thiadiazoles also [3,2-a] quinazoline-6, the structure of 7-diketone, then uses the MMFF94 field of force to be optimized with ChemBio3DUltra12.0.NQO1 (PDBID:2F1O) and compound all use AutodockTools1.5.6 to be converted into PDBQT form.Autodockvina1.1.2 is adopted to carry out molecular Docking Study.The coordinate of NQO1 is set to: center_x=11.549, center_y=11.875, center_z=-6.018; Size_x=15, size_y=15, size_z=15.Parameter exhaustiveness is set to 20.Except special instruction, other parameters all adopt default value.Finally, choose the highest conformation PyMoL1.7 of marking value and carry out interpretation of result (Fig. 1).Found out by Fig. 1, compound is in parallel state with coenzyme F AD, forms strong pi-pi accumulation effect.The 3-position methyl of compound is in a hydrophobic pocket be made up of amino-acid residue Met151, Phe236, His161 and Met131, forms strong hydrophobic interaction.In addition, the main phase mutual effect between hydrogen bond and NQO1.Detailed analysis can obtain, the 1-position sulphur atom of compound can form interaction of hydrogen bond with amino-acid residue His161, the 6-position ketonic oxygen of compound can form interaction of hydrogen bond with amino-acid residue Tyr128, and the ketonic oxygen of 7-position can form dual hydrogen bond action with amino-acid residue Tyr126 and Tyr128.The more important thing is, the 5-interdigit aminomethyl phenyl part of compound is parallel to the phenyl ring part of residue Tyr128, forms strong pi-pi accumulation effect.
Embodiment 4 topoisomerase I Inhibition test
The activity of TopoI enzyme is judged by the relaxation cases of observation superhelix pBR322DNA, the DNATopoI of 1 unit is defined as 37 DEG C, under standard reaction condition, through the amount of the TopoI needed for 30 minutes completely lax 0.5 μ g negative supercoiling pBR322 DNA.Testing sample first dissolves with DMSO, by the required solution to be measured being diluted to different concns, makes final concentration be respectively 400 μMs, 200 μMs, 100 μMs, 50 μMs, and camptothecine same method dilutes, final concentration 200 μMs.Reaction mixture (10 μ L), comprises H
2o(6.5 μ L), 10 × DNATopoIBuffer(1 μ L), 0.1%BSA(1 μ L), DNATopoI(0.5U), the testing sample (1 μ L) of pBR322DNA (0.25 μ g), different concns.After adding above-mentioned reaction mixture, centrifugation makes various uniform composition mix, and the while of afterwards, constant temperature 30 minutes, adds reaction terminating liquid (10 × LoadingBuffer, 1 μ L) stopped reaction respectively; On the sepharose of 1%, in tbe buffer liquid, electrophoresis 2 hours under 75V constant-pressure conditions, the gel ethidium bromide solution of 1 μ g/mL dyes 30 minutes, finally observes electrophoresis result with gel imaging system and takes a picture.Compound can suppress the activity (Fig. 2) of TopoI enzyme completely at 200 μMs.
Accompanying drawing illustrates: Fig. 1 is the molecular docking of aminomethyl phenyl-2-methyl-5H-benzo [i] [1,3,4] thiadiazoles also [3,2-a] quinazoline-6,7-diketone and NQO1 between 5-, and wherein dotted line is the hydrogen bond formed.
Fig. 2 be between 5-aminomethyl phenyl-2-methyl-5H-benzo [i] [1,3,4] thiadiazoles also [3,2-a] quinazoline-6,7-diketone on the impact of topoisomerase I activity, wherein A road: pBR322DNA; B road: pBR322DNA+0.5UTOPOI enzyme; C road: pBR322DNA+0.5UTOPOI enzyme+camptothecine 200 μMs; Aminomethyl phenyl-2-methyl-5H-benzo [i] [1,3,4] thiadiazoles also [3,2-a] quinazoline-6,7-diketone (difference 400,200,100,50 μMs) between D, E, F, G road pBR322DNA+0.5UTOPOI enzyme+5-.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (3)
1. an adjacent naphthoquinone derivatives, is characterized in that, it is for having the compound of structure shown in formula I:
(I)。
2. prepare the method for adjacent naphthoquinone derivatives described in claim 1, it is characterized in that, by reactant 2-hydroxyl-1,4-naphthoquinones, 3-tolyl aldehyde, 5-methyl-2-amino-1,3,4-thiadiazoles and appropriate DMF join in round-bottomed flask, at 130 DEG C of reacting by heating 5-8 hour, after reacting completely, gained mixture is cooled to room temperature, adds water washing, sedimentation and filtration, column chromatography purification, to obtain between target compound 5-aminomethyl phenyl-2-methyl-5H-benzo [i] [1,3,4] thiadiazoles also [3,2-a] quinazoline-6,7-diketone.
3. the compound of claim 1 is for the preparation of the purposes of medicine for the treatment of malignant tumour.
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| CN108794419A (en) * | 2018-08-28 | 2018-11-13 | 中南大学 | Naphtho- [2,3-b] isoxazole -4,9- derovatives and preparation method and purposes |
| CN108794419B (en) * | 2018-08-28 | 2022-07-05 | 中南大学 | Naphtho [2,3-b ] isoxazole-4, 9-diketone derivative and preparation method and application thereof |
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